4. Place the product vial on an even and firm surface. Invert
the diluent vial with the Mix2Vial set attached and push the
spike of the transparent adapter end straight down
through the product vial stopper. The diluent will automati
cally flow into the product vial.
4
5. With one hand grasp the productside of the Mix2Vial set
and with the other hand grasp the diluentside and
unscrew the set carefully into two pieces to avoid excessive
foam building when dissolving the product. Discard the
diluent vial with the blue Mix2Vial adapter attached.
5
6. Gently swirl the product vial with the transparent adapter
attached until the substance is fully dissolved. Do not
shake.
6
7. Draw air into an empty, sterile syringe. While the product
vial is upright, connect the syringe to the Mix2Vial´s Luer
Lock fitting. Inject air into the product vial.
7
UNDESIRABLE EFFECTS
Hypersensitivity or allergic reactions (which may include angioedema, stinging, burning
(irritation), or phlebitis at the injection/infusion site, chills, flushing, generalised urticaria,
headache, hives, hypotension, lethargy, nausea, restlessness, tachycardia, tightness of
the chest, tingling, vomiting, wheezing) have been observed infrequently in patients
treated with factor X/IX containing products. In some cases of haemophilia B, these
reactions have progressed to severe anaphylaxis, and they have occurred in close
temporal association with development of factor IX inhibitors (see also “Special
warnings and special precautions for use”).
Nephrotic syndrome has been reported following attempted immune tolerance
induction in haemophilia B patients with factor IX inhibitors and a history of allergic
reaction.
In case of massive therapy the patient should be monitored for symptoms of hyper
volemia.
On rare occasions, fever has been observed.
Patients may develop neutralising antibodies (inhibitors) to factor X/IX. If such inhibitors
occur, the condition will manifest itself as an insufficient clinical response. In such cases,
it is recommended that a specialised haemophilia centre be contacted. In a clinical study
in 14 previously untreated patients (PUPs) with hemophilia B no cases of development
of inhibitors were reported.
There is a potential risk of thromboembolic episodes following the administration of
factor X/IX products, with a higher risk for low purity preparations. The use of low
purity factor X/IX products has been associated with instances of myocardial infarction,
disseminated intravascular coagulation, venous thrombosis and pulmonary embolism.
The use of high purity factor X/IX is rarely associated with such side effects.
For information on viral safety see “Special warnings and special precautions for use”.
STORAGE AND STABILITY
Factor X P Behring is to be stored at +2 to +8 °C. Do not freeze.
Store in the closed carton!
Upon reconstitution, it is advisable to administer Factor X P Behring immediately; in any
case the reconstituted solution should be administered within 8 hours in order to assure
sterility.
Keep out of the reach of children!
LICENSE NUMBER
47’726
On prescription only (嗱)
Withdrawal
8. While keeping the syringe plunger pressed, invert the
system upside down and draw the concentrate into the
syringe by pulling the plunger back slowly.
8
9. Now that the concentrate has been transferred into the
syringe, firmly hold on to the barrel of the syringe (keeping
the syringe plunger facing down) and disconnect the trans
parent Mix2Vial adapter from the syringe.
9
For injection of Factor X P Behring the use of plastic disposable syringes is recommended
as the ground glass surfaces of allglass syringes tend to stick with solutions of this type.
Method of administration
– Administer slowly intravenously at a rate comfortable to the patient (max. 2 ml/min)
via either intravenous injection using a suitable injection needle or intravenous
infusion by means of a winged infusion set.
– It has to be taken care that no blood enters the syringe filled with product.
– Observe the patient for any immediate reaction. If any reaction takes place that is
thought to be related to the administration of Factor X P Behring the rate of infusion
should be decreased or the infusion stopped, as required by the clinical condition of
the patient (see also “Special warnings and special precautions for use”).
DATE OF LAST REVISION
July 2010
Dear Patient,
This leaflet gives you important information about this medicine. It is conti
nually updated. Therefore, please read this leaflet carefully. Unfortunately,
one cannot explain all the medical knowledge relating to your disease in such a
small leaflet. This is why you might not understand every part of it without a
comprehensive medical background or a personal explanation from your doctor.
For this reason this leaflet also provides specialized information for your doctor,
so that he can help you to understand.
If you have further questions about this medicine or any questions about your
disease, please ask your doctor or pharmacist.
Factor X P Behring
Powder and solvent for solution for injection or infusion
QUALITATIVE AND QUANTITATIVE COMPOSITION
Factor X P Behring is presented as a powder and solvent for solution for injection
or infusion containing nominally 600 − 1200 IU human coagulation factor X and
600 IU human coagulation factor IX per vial.
The product reconstituted with 20 ml of water for injections contains approxi
mately 30 – 60 IU/ml human coagulation factor X and 30 IU/ml human
coagulation factor IX.
The specific activity of Factor X P Behring is 4 – 60 IU factor X/mg protein and
3 – 38 IU factor IX/mg protein.
Other ingredients
Antithrombin III, Heparin, Aminoacetic acid, calcium chloride, sodium chloride,
sodium citrate, HCl or NaOH (in small amounts for pH adjustment)
Factor X P Behring does not contain a preservative.
Supplied solvent:
Water for injections 20 ml
PHARMACEUTICAL FORM AND PRESENTATIONS
Refererences:
1. Auerswald G, Auberger K, Kurnik P, Heilmeier T, Münchow N. Therapy in eight children with
congenital Factor X deficiency. Blood 92 (10) Supplement 1: 358a; 1998
2. Auerswald D. Prophylaxis in Rare Coagulation Disorders – Factor X Deficiency. Thromb Res,
118 (Suppl. 1): S29S31; 2006
3. Lechler E. Use of Prothrombin Complex Concentrates for Prophylaxis and Treatment of Bleeding
Episodes in Patients with Heriditary Deficiency of Prothrombin, Factor VII, Factor X, Protein C,
Protein S, or Protein Z. Thrombosis Research 95: S39S50; 1999
4. Roberts HR & White GC. Inherited Disorders of Prothrombin Conversion. In: Colman RW Hirsh J,
Marder VJ, Clowes AW, George JN (eds): Hemostasis and Thrombosis – Basic Principles and
Clinical Practice. 4th Ed., pp 839853, JB Lippincott Company, Philadelphia, 2001
5. Seligssohn U & White GC. Inherited deficiencies of coagulation Factors II, V, VII, XI, and XIII and
the combined deficiencies of Factors V and VIII and of the Vitamin Kdependent Factors. In: Beutler E,
Lichtman MA, Coller BS, Kipps TJ, Seligson U (eds): Williams HEMATOLOGY (6th ed) McGraw Hill,
New York, pp 16391657, 2001
6. Perry DJ. Factor X and its Deficiency States. Haemophilia, 3: 159172; 1997
7. Herrmann FH, Auerswald G, RuizSaez A, Navarrete M, Pollmann H, Lopaciuk S, Batorova A, Wulff K.
Factor X Deficiency: Clinical Manifestation of 102 Subjects from Europe and Latin America with
Mutations in the Factor X Gene. Haemophilia, 12: 479489; 2006
8. Kumar M, Mehta P. Congenital Coagulopathies and Pregnancy: Report of Four Pregnancies in a
Factor X Deficient Woman. Am J Hematol, 46: 241244; 1994
Pharmaceutical form
Powder and solvent for solution for injection or infusion.
Presentations
One pack with 600 − 1200 IU FX / 600 IU FIX containing:
1 vacuum vial with dried substance
1 vial with 20 ml water for injections
One device pack containing:
1 filter transfer device 20/20
1 disposable 20 ml syringe
1 venipuncture set
2 alcohol swabs
1 nonsterile plaster
PHARMACOTHERAPEUTIC GROUP
Antihaemorrhagics: blood coagulation factor IX.
ATC code: B02B D04
NAME AND ADDRESS OF THE MARKETING AUTHORIZATION HOLDER
CSL Behring AG
Wankdorfstrasse 10
3000 Bern 22
Switzerland
THERAPEUTIC INDICATIONS
Treatment and prophylaxis of bleeding in patients with
− haemophilia B (congenital factor IX deficiency)
− other diseases with factor IX and/or factor X deficiency
CONTRAINDICATIONS
Hypersensitivity to the active substance or to any of the excipients.
High risk of thrombosis or disseminated intravascular coagulation (see also
“Special warnings and special precautions for use”).
In case of recent thrombosis or recent myocardial infarction the risk of the
therapy is to be weighed against that of nontreatment.
5
6
A5758 G26 A
1
Present or past evidence of an allergic response to heparin, causing a fall in the
number of blood platelets (Heparinassociated thrombocytopenia Type II, HAT
Type II).
Pregnancy and lactation
Animal reproduction studies have not been conducted with factor X/IX. Based on
the small number of patients with FX deficiency and the rare occurrence of
haemophilia B in women, experience regarding the use of Factor X P Behring
during pregnancy and breastfeeding is not available. But single case reports from
women with FX deficiency indicate a positive effect of FX substitution for the
outcome of pregnancy (8).
Therefore, factor X/IX should be used during pregnancy and lactation only if
clearly indicated.
SPECIAL WARNINGS AND SPECIAL PRECAUTIONS FOR USE
As with any intravenous protein product, allergic type hypersensitivity reactions
are possible. Factor X P Behring contains human proteins other than factor X/IX.
Patients should be informed of the early signs of hypersensitivity reactions inclu
ding hives, generalised urticaria, tightness of the chest, wheezing, hypotension,
and anaphylaxis. If these symptoms occur, they should be advised to discontinue
use of the product immediately and contact their physician.
In case of shock, the current medical standards for shocktreatment should be
observed.
After repeated treatment with human coagulation factor X/IX products, patients
should be monitored for the development of neutralising antibodies (inhibitors)
that should be quantified in Bethesda Units (BU) using appropriate biological
testing.
There have been reports in the literature showing a correlation between the
occurrence of a factor IX inhibitor and allergic reactions. Therefore, patients
experiencing allergic reactions should be evaluated for the presence of an
inhibitor. It should be noted that patients with factor IX inhibitors may be at an
increased risk of anaphylaxis with subsequent challenge with factor IX.
Because of the risk of allergic reactions with factor X/IX concentrates, the initial
administrations of factor X/IX should, according to the treating physician’s
judgement, be performed under medical observation where proper medical care
for allergic reactions could be provided.
Since the use of factor X/IX complex concentrates has historically been associated
with the development of thromboembolic complications, the risk being higher in
low purity preparations, the use of factor X/IXcontaining products may be
potentially hazardous in patients with signs of fibrinolysis and in patients with
disseminated intravascular coagulation (DIC). Because of the potential risk of
thrombotic complications, clinical surveillance for early signs of thrombotic and
consumptive coagulopathy should be initiated with appropriate biological testing
when administering this product to patients with liver disease, to patients
postoperatively, to newborn infants or to patients at risk of thrombotic
phenomena or DIC. In each of these situations, the benefit of treatment with
Factor X P Behring should be weighed against the risk of these complications.
When medicinal products prepared from human blood or plasma are adminis
tered, infectious diseases due to the transmission of infective agents can not be
totally excluded. This also applies to pathogens of unknown nature. In order to
prevent such infections the following standard measures have been taken:
• selection of donors,
• screening of individual donations and plasma pools for specific markers of
infection,
• the inclusion of effective manufacturing steps for the inactivation/removal of
viruses.
The measures taken are considered effective for enveloped viruses such as HIV,
HBV and HCV and for the nonenveloped virus HAV. The measures taken may be
of limited value against nonenveloped viruses such as parvovirus B19.
Parvovirus B19 infection may be serious for pregnant women (fetal infection) and
for individuals with immunodeficiency or increased erythropoiesis (e.g. haemo
lytic anaemia).
Vaccination against hepatitis A and hepatitis B should be generally considered for
patients in regular/repeated receipt of human plasmaderived factor X/IX products.
It is strongly recommended that every time that Factor X P Behring is administered
to a patient, the name and batch number of the product are recorded in order to
maintain a link between the patient and the batch of the product.
INTERACTIONS WITH OTHER MEDICINAL PRODUCTS AND OTHER FORMS
OF INTERACTIONS
No interactions of human coagulation factor X/IX products with other medicinal
products are known.
Incompatibilities
This medicinal product must not be mixed with other medicinal products, except
for normal saline.
Dosage
The dosage and duration of the substitution therapy depend on the severity of the
factor X/factor IX deficiency, on the location and extent of the bleeding and on the
patient’s clinical condition.
F X deficiency:
Due to the rarity of the disease, no clinical studies with Factor X P Behring have been
performed in subjects with FX deficiency. Therefore recommendations on dosage are
based on information available in the literature (1–6), mainly data derived from
treatment of FXdeficient subjects with plasma or prothrombin complex.
Dosage and duration of the substitution therapy depend on the severity of the factor X
deficiency, on the location and extent of the bleeding. The amount to be administered
should always be oriented to the clinical effectiveness in the individual case.
One International Unit (IU) of Factor X activity is equivalent to that quantity of FX in one
ml of normal human plasma. The calculation of the required dose of Factor X is based
on the empirical finding that one unit FX per kg body weight raises the plasma factor X
activity by approximately 1.5 % of normal activity. The required dosage is determined
using the following formula:
Required units = body weight [kg] x desired factor X rise [% or IU/dl] x 0.7
Plasma levels between 10 to 40 % have been described as hemostatically effective
(3–5). Based on the halflife of 24 to 40 hours, administration of FX every 24 hours
should generally be sufficient if continued treatment is needed. Roberts & White (4)
advise to avoid FX levels over 50 % due to the risk of thrombosis. During the course of
treatment, appropriate determination of factor X levels is advised to guide the dose to
be administered and the frequency of repeated infusions. In the case of major surgical
interventions in particular, precise monitoring of the substitution therapy by means of
coagulation analysis (plasma factor X activity) is indispensable. Individual patients may
vary in their response to factor X, achieving different levels of in vivo recovery and
demonstrating different halflives.
Prophylactic treatment in infants and young children has been described in the
literature, with up to 40 IU/kg of Prothrombin Complex Concentrates every 3 to 10 days
(3) or 20 to 40 IU of Factor X per kg body weight once to twice a week (1,2).
Factor IX deficiency:
The number of units of factor IX administered is expressed in International Units (IU),
which are related to the current WHO standard for factor IX products. Factor IX actvity
in plasma is expressed either as a percentage (relative to normal human plasma) or in
International Units (relative to an international standard for factor IX in plasma).
One International Unit (IU) of factor IX activity is equivalent to that quantity of factor IX
in one ml of normal human plasma. The calculation of the required dosage of factor IX
is based on the empirical finding that 1 IU factor IX per kg body weight raises the
plasma factor IX activity by 1.0 % of normal activity. The required dosage is determined
using the following formula:
Required units = body weight [kg] x desired factor IX rise [% or IU/dl] x 1.0*
The amount to be administered and the frequency of administration should always be
oriented to the clinical effectiveness in the individual case. Factor IX products rarely
require to be administered more than once daily.
In the case of the following haemorrhagic events, the factor IX activity should not fall
below the given plasma activity level (in % of normal or IU/dl) in the corresponding
period. The following tables can be used to guide dosing in bleeding episodes and
surgery:
Degree of haemorrhage/
Type of surgical procedure
Haemorrhage
Early haemarthrosis,
muscle bleeding or oral
bleeding
Factor IX level required
(% or IU/dl)
Frequency of doses (hours)/
Duration of therapy (days)
20 – 40
Repeat every 24 hours.
At least 1 day, until the
bleeding episode as indi
cated by pain is resolved
or healing is achieved.
Repeat infusion every 24
hours for 3 – 4 days or
more until pain and acute
disability are resolved.
Repeat infusion every
8 to 24 hours until threat
is resolved.
More extensive
haemarthrosis, muscle
bleeding or haematoma
30 – 60
Lifethreatening
haemorrhages
60 – 100
Surgery
Minor
including tooth extraction
Major
DOSAGE AND ADMINISTRATION
Treatment should be initiated under the supervision of a physician experienced in
the treatment of haemophilia.
30 – 60
80 – 100
(pre and postoperative)
During the course of treatment, appropriate determination of factor IX levels is advised
to guide the dose to be administered and the frequency of repeated infusions. In the
case of major surgical interventions in particular, precise monitoring of the substitution
therapy by means of coagulation analysis (plasma factor IX activity) is indispensable.
Individual patients may vary in their response to factor IX, achieving different levels of
in vivo recovery and demonstrating different halflives.
For longterm prophylaxis against bleeding in patients with severe haemophilia B, the
usual doses are 20 to 40 IU of factor IX per kg body weight at intervals of 3 to 4 days.
In some cases, especially in younger patients, shorter dosage intervals or higher doses
may be necessary.
Patients should be monitored for the development of factor IX inhibitors. If the
expected factor IX activity plasma levels are not attained, or if bleeding is not controlled
with an appropriate dose, an assay should be performed to determine if a factor IX
inhibitor is present. In patients with high levels of inhibitor, factor IX therapy may not be
effective and other therapeutic options should be considered. Management of such
patients should be directed by physicians with experience in the care of patients with
haemophilia.
See also section “Special warnings and special precautions for use”
There are insufficient data to recommend the use of Factor X P Behring in children less
than 6 years of age.
Overdose
No symptoms of overdose with human coagulation factor X/IX have been reported.
Administration
General instructions
– Do not use after expiry date given on the pack and container.
– The powder must be mixed (reconstituted) with the diluent (liquid) and withdrawn
from the vial under aseptic conditions.
– The solution should be clear or slightly opalescent i.e. it might be sparkling when held
up to the light but must not contain any obvious particles. After filtering or with
drawal (see below) the solution should be checked by eye for small particles and
discoloration, before it is administered.
– Do not use the solution if it is visibly cloudy or if it contains flakes or particles.
– Any unused product or waste material should be disposed of in accordance with local
requirements and as instructed by your doctor.
Reconstitution:
Without opening either vial, warm the Factor X P Behring powder and the solvent to
room temperature. This can be done either by leaving the vials at room temperature for
about an hour, or by holding them in your hands for a few minutes. DO NOT expose the
vials to direct heat. The vials must not be heated above body temperature (37 °C).
Carefully remove the protective caps from the diluent vial and the product vial. Clean
the exposed rubber stoppers of both vials with one alcohol swab each and allow them
to dry. The diluent can now be transferred to the powder with the administration set
(Mix2Vial) attached. Please follow the instructions given below.
1. Open the Mix2Vial package by peeling away the lid. Do not
remove the Mix2Vial from the blister package!
1
2. Place the diluent vial on an even, clean surface and hold the
vial tight. Take the Mix2Vial together with the blister pack
age and push the spike of the blue adapter end straight
down through the diluent vial stopper.
2
3. Carefully remove the blister package from the Mix2Vial set
by holding at the rim, and pulling vertically upwards.
Make sure that you only pull away the blister package and
not the Mix2Vial set.
Every 24 hours, at least
1 day, until healing is
achieved.
Repeat infusion every
8 – 24 hours until
adequate wound healing,
then therapy for at least
another 7 days to maintain
a factor IX activity of 30 %
to 60 % (IU/dl).
3
* reciprocal of observed recovery
2
3
4